Project Summary Over 100 million Americans suffer from chronic pain, which is greater than cardiovascular disease, cancer, and diabetes combined. Current strategies for treating persistent pain address the symptomology but not the underlying pathology and often are ineffective. Defining the cellular mechanisms that mediate inflammatory signaling, a key contributor to the development of chronic pain, is likely to provide new pharmacological strategies for treating chronic pain. For the first time, utilizing pharmacological inhibition and genetic deletion of cathepsin K our laboratory has demonstrated a novel link between cathepsin K activity and inflammatory-induced peripheral nociception in the mouse. Based upon our preliminary work we hypothesize a novel role for cathepsin K, a cysteine peptidase traditionally known for its importance in osteoclast-mediated bone resorption, in mediating inflammatory-induced nociception. The objective of our proposal is to determine whether cathepsin K inhibitors can be utilized as novel analgesics. This project will utilize molecular, electrophysiological, and behavioral techniques in mice to address three aims in the pursuit of our objective: 1) Define the therapeutic parameters by which cathepsin K inhibition alleviates peripheral nociception; 2) Determine if inhibition of cathepsin K activity prevents the development and/or maintenance of neuropathic nociception; and 3) Define the dynamic changes in cathepsin K regulation after nociception. We anticipate that we will validate our preliminary findings and show that cathepsin K mediates inflammatory-induced peripheral nociception and define how cathepsin K is mediating nociception. Virtually nothing is known regarding the role cathepsin K plays in inflammation and nociception. Our laboratory?s novel observation presents with an exciting opportunity to advance the scientific community?s fundamental understanding of how inflammation mediates nociception. Consequently, our work may provide new therapeutic targets to treat the more than 100 million Americans suffering from chronic pain.